Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial

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Hair and Claw Dehydroepiandrosterone Concentrations in Newborn Puppies Spontaneously Dead within 30 Days of Age

The latest intrauterine fetal developmental stage and the neonatal period represent the most challenging phases for mammalian offspring. Toward the term of pregnancy, during parturition, and after birth, the hypothalamic–pituitary–adrenal axis (HPA) is a key system regulating several physiologic processes, through the production of cortisol and dehydroepiandrosterone (DHEA). This study was aimed to assess DHEA concentrations in hair and claws of 126 spontaneously dead newborn puppies, classified as premature puppies (PRE-P), stillborn puppies (STILL-P) and puppies that died from the 1st to the 30th day of life (NEON-P). The possible influence of newborn sex, breed body size, and timing of death on DHEA concentrations in both matrices was evaluated. Claw DHEA concentrations were higher in the PRE-P group when compared to STILL-P and NEON-P puppies (p < 0.05), whilst no significant differences were found in hair for all the studied factors. The results confirm the hypothesis that higher amounts of DHEA are produced during the intrauterine life in dogs, also in puppies that will die soon after birth

How stressful is maternity? Study about cortisol and dehydroepiandrosterone-sulfate coat and claws concentrations in female dogs from mating to 60 days post-partum

In dogs, the phase from mating to the end of weaning lasts about 120 days and encompasses many aspects that, interacting, contribute to increase the allostatic load. The coat and claws, useful for long-term change assessments, have the advantage of being collectable without invasiveness. In the present study, the Cortisol (C) and Dehydroepiandrosterone-sulfate (DHEA-S) concentration monthly changes in the coat and claws were studied in female dogs from mating to the end of weaning to assess Hypothalamic\u2013Pituitary\u2013Adrenal (HPA) axis activation during pregnancy and the post-partum period. The results from 15 Dobermann Pinscher female dogs showed a trend of increase of the coat C from mating to 60 days post-partum, with significant changes between mating and parturition-60 days post-partum (p < 0.01) and between the 30-day pregnancy diagnosis (PD) and 30\u201360 days post-partum (p < 0.05). The claws C trend showed significant increases between mating and 30\u201360 days post-partum (p < 0.05) and between the PD and 60 days post-partum (p < 0.01). DHEA-S in both matrices showed non-significant changes. The results suggest that maternity could play a pivotal role in the HPA axis activation, with a subsequent chronic secretion of C determining an increase in the allostatic load in the mothers. Neither maternal parity nor litter size played a significant role in the accumulation of C and DHEA-S in both matrices

A new option for early breast cancer patients previously irradiated for Hodgkin's disease: intraoperative radiotherapy with electrons (ELIOT)

Introduction Patients who have undergone mantle radiotherapy for Hodgkin's disease (HD) are at increased risk of developing breast cancer. In such patients, breast conserving surgery (BCS) followed by breast irradiation is generally considered contraindicated owing to the high cumulative radiation dose. Mastectomy is therefore recommended as the first option treatment in these women. Methods Six patients affected by early breast cancer previously treated with mantle radiation for HD underwent BCS associated with full-dose intraoperative radiotherapy with electrons (ELIOT). Results A total dose of 21 Gy ( prescribed at 90% isodose) in five cases and 17 Gy ( at 100% isodose) in one case were delivered directly to the mammary gland without acute complications and with good cosmetic results. After an average of 30.8 months of follow up, no late sequelae were observed and the patients are free of disease. Conclusion In patients previously irradiated for HD, ELIOT can avoid repeat irradiation of the whole breast, permit BCS and decrease the number of avoidable mastectomies

High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel

Summary Background: Clinically overt central nervous system (CNS) involvement occurs in 10%-15% of patients with advanced breast cancer. Patients and methods: The International Breast Cancer Study Group (IBCSG) conducted a dose-finding phase I trial of epirubicin (E) and docetaxel (D) as first-line therapy in advanced breast cancer patients. The study was expanded into a phase II at the recommended doses of E 90 mg/m2and D 75 mg/m2every three weeks. From July 1996 to May 1998, a total of 92 patients (median age 50 years) entered the two studies. Results: Twenty-eight out of ninety-two patients treated with the combination of E and D (30%) developed CNS metastases (95% confidence limits, 26%-35%), which were cerebral in twenty-five patients, leptomeningeal in two, and both in one. Of these 28 patients, 19 (68%) had an objective response. Median time for the development of CNS metastases from the start of chemotherapy was 15 months (range 5-42), if excluding the 6 patients presenting CNS progression within 3 months from start of treatment. It is notable that 11 patients (39%) had progression in the CNS only. Median survival from appearance of brain metastases in the whole group was only three months (range 1-22). C-erbB-2 overexpression was found in 14 out of 16 patients (87%) in whom the assay was performed (3+ in 10, 2+ in 1 and 1+ in 3 cases). Conclusions: As anthracycline- and taxane-containing regimens are increasingly used both in the metastatic and in the adjuvant setting, a careful monitoring of any neurological symptom is advisable. Our preliminary observation on the possible increase of incidence of CNS involvement in patients with advanced breast cancer receiving this effective drug combination requires further evaluatio

The ionization of Mg by electron impact at 1000 eV studied by (e, 2e) experiments

The ionization of Mg 3s and 2p and He 1s has been studied in (e, 2e) experiments at about 1000 eV incident energy and 20 eV ejected electron energy for a momentum transfer between 0.5 and 2.1 au. The comparison with the predictions of the distorted wave Born approximation model shows a generally good agreement between experiment and theory. The differences observed between the He and Mg angular distributions can be explained as an initial state effect and are attributed to the differences between the He 1s and Mg 3s wavefunctions in the momentum space

The impact of loco-regional recurrences on metastatic progression in early-stage breast cancer: a multistate model

To study whether the effects of prognostic factors associated with the occurrence of distant metastases (DM) at primary diagnosis change after the incidence of loco-regional recurrences (LRR) among women treated for invasive stage I or II breast cancer. The study population consisted of 3,601 women, enrolled in EORTC trials 10801, 10854, or 10902 treated for early-stage breast cancer. Data were analysed in a multivariate, multistate model by using multivariate Cox regression models, including a state-dependent covariate. The presence of a LRR in itself is a significant prognostic risk factor (HR: 3.64; 95%-CI: 2.02-6.5) for the occurrence of DM. Main prognostic risk factors for a DM are young age at diagnosis (</=40: HR: 1.79; 95%-CI: 1.28-2.51), larger tumour size (HR: 1.58; 95%-CI: 1.35-1.84) and node positivity (HR: 2.00; 95%-CI: 1.74-2.30). Adjuvant chemotherapy is protective for a DM (HR: 0.66; 95%-CI: 0.55-0.80). After the occurrence of a LRR the latter protective effect has disappeared (P = 0.009). The presence of LRR in itself is a significant risk factor for DM. For patients who are at risk of developing LRR, effective local control should be the main target of therapy

Identification of RAD51-BRCA2 Inhibitors Using N-Acylhydrazone-Based Dynamic Combinatorial Chemistry

RAD51 is an ATP-dependent recombinase, recruited by BRCA2 to mediate DNA double-strand breaks repair through homologous recombination and represents an attractive cancer drug target. Herein, we applied for the first-time protein-templated dynamic combinatorial chemistry on RAD51 as a hit identification strategy. Upon design of N-acylhydrazone-based dynamic combinatorial libraries, RAD51 showed a clear templating effect, amplifying 19 N-acylhydrazones. Screening against the RAD51-BRCA2 protein-protein interaction via ELISA assay afforded 10 inhibitors in the micromolar range. Further 19F NMR experiments revealed that 7 could bind RAD51 and be displaced by BRC4, suggesting an interaction in the same binding pocket of BRCA2. These results proved not only that ptDCC could be successfully applied on full-length oligomeric RAD51, but also that it could address the need of alternative strategies toward the identification of small-molecule PPI inhibitors

Geographical distribution of e-cadherin germline mutations in the context of diffuse gastric cancer: A systematic review

Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by CDH1 germline mutations. Nevertheless, current CDH1 genetic screening recommendations disregard an unbalanced worldwide distribution of CDH1 variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing CDH1 variants in gastric cancer patients originating from both highand low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that CDH1 mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of CDH1 alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of CDH1 variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for CDH1 genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease.This manuscript was supported by the Italian Ministry of Health (Project Code GR‐2016‐ 02361655) and was partially supported by the Ricerca Corrente and 5 × 1000 funds, and financed by FEDER funds through the Operational Programme for Competitiveness Factors (COMPETE 2020), Programa Operacional de Competitividade e Internacionalização (POCI) and Programa Operacional Regional do Norte (Norte 2020); and by the Portuguese Foundation for Science and Technology (FCT projects PTDC/MED‐GEN/30356/2017 and PTDC/BIM‐ONC/0281/2014). We acknowledge the American Association of Patients with Hereditary Gastric Cancer “No Stomach for Cancer” for funding Figueiredo’s research